A key goal of modern molecular oncology is identifying the underlying genetic and genomic variations that characterize a given tumor so that the patient can receive targeted therapy with chemotherapeutic agents likely to provide the most benefit. Breast cancer is the most common form of cancer among women in the Western World, with an estimated 1 million new diagnoses and 400,000 deaths per year worldwide (1). The advent of targeted therapies such as Tamoxifen for estrogen receptor positive cancer (2) and Herceptin for tumors harboring amplification of the HER2 oncogene (3) has had significant impact on patient survival, yet various chemotherapy regimens still form an important component of breast cancer treatment (4). Breast cancer is a heterogeneous disease with distinct molecular subtypes characterized by differential response to targeted and chemotherapeutic agents. While chemotherapy is a successful treatment regimen in many cases, an estimated 50% of patients fail to benefit due to intrinsic or acquired multidrug resistance (1). Multidrug resistance (MDR) refers to the resistance of cancer cells to multiple classes of chemotherapeutic drugs that can be structurally and mechanistically unrelated and is related to the overexpression of a variety of proteins that act as ATP-dependent efflux pumps (5). Understanding the molecular alterations that contribute to MDR in breast cancer is a crucial first step in enabling the development of diagnostic tests capable of predicting resistance to a given therapy and rationally selecting more efficacious therapeutic agents.
ABCC3 overexpression has been implicated in acquired multidrug resistance in cancer cell lines in previous studies. For instance, Liu et al report 459-fold overexpression of ABCC3 relative to the parental in a cell line, MCF-7/AdVp3000, that was derived by selection for growth in the presence of doxorubicin (36). In addition, it has recently been shown that treatment of carcinoma cell lines with vincristine results in significant upregulation of ABCC2 and ABCC3 transcripts in these cells (37). The related pumps ABCC2(MRP2) and ABCC10 (MRP7) have both been shown to confer paclitaxel resistance when overexpressed (38) (39), and ABCC2 has been shown to be an important determinant of paclitaxel pharmacokinetics in vivo in mouse models (40). Paclitaxel has not been previously demonstrated to be a substrate for ABCC3 and indeed studies of ectopic overexpression of ABCC3 in MDCK or NIH-3T3 cells have failed to demonstrate increased resistance to paclitaxel (41, 42). Notably, it was also found (41) that ABCC3 cannot confer resistance to doxorubicin in long term assays despite other published reports of functional studies suggesting a role for ABCC3 in transporting this agent (36).
These various observations illustrate the fact that breast cancer is a heterogeneous disease that can evade chemotherapy through multiple mechanisms and highlight the need for panels of biomarkers that can be used to predict therapeutic response in individual cancer patients.